Modeling the Extracellular Matrix-like Retinal Protein Pikachurin and Its Binding to α-Dystroglycan and GPCR (GPR179)

Modeling the Extracellular Matrix-like Retinal Protein Pikachurin and Its Binding to α-Dystroglycan and GPCR (GPR179)

Alvin Sherman Library

Pikachurin is an extracellular matrix scaffold protein that links photoreceptor and ON-bipolar cell synapses by bridging the presynaptic dystroglycan complex and the postsynaptic receptor GPR179, ensuring precise synaptic alignment required for vision. Although its role in dystroglycanopathy associated visual phenotypes is well recognized, there is no published structural model showing how pikachurin engages α-dystroglycan or how this may influence GPCR linked synaptic signaling. This study computationally modeled full length Pikachurin using the complete nucleic acid sequence and available Protein Data Bank structures, integrating Jmol, AlphaFold, and literature-based analysis to predict domain organization, Ca²⁺-binding motifs, and glycan interaction sites with dystroglycan. The resulting model incorporates Fibronectin Type III (FN3 I, FN3 II) and Laminin G-like (LG1, LG2, LG3) domains, including a Ca²⁺-binding site between LG1 and LG2 predicted to mediate high-affinity binding to glycosylated dystroglycan. Guided by these predictions, a physical 3D printed model was constructed in which a polysaccharide derived from PDB ID 7ZCB is attached at the Asn47 binding site, and a dystroglycan-derived polysaccharide is positioned at the Ca²⁺-dependent glycan-binding interface. A dystroglycan polysaccharide is also printed and attached to the expected calcium-binding site between the LG1 and LG2 domains. The residues (within the LG3 domain) that bind with a GPCR (GPR179) into the postsynaptic membrane are also highlighted. With this 3D molecular model, we are better able to understand and explain the story of how Pikachurin is embedded in the extracellular matrix and connected to the presynaptic neuron.